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Background  From earlier studies it is known that the  APOE  ε2/ε3/ε4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid 1–42  (Aβ42) in patients with cognitive decline due to Alzheimer’s disease (AD), as well as in cognitively healthy controls. Here, in a large cohort consisting solely of cognitively healthy individuals, we aimed to evaluate how the effect of  APOE  on CSF Aβ42 varies by age, to understand the association between  APOE  and the onset of preclinical AD.    Methods    APOE  genotype and CSF Aβ42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17–99 from nine different clinical research centers.    Results  CSF concentrations of Aβ42 were lower in  APOE  ε4 carriers than in noncarriers in a gene dose-dependent manner. The effect of  APOE  ε4 on CSF Aβ42 was age dependent. The age at which CSF Aβ42 concentrations started to decrease was estimated at 50 years in  APOE  ε4-negative individuals and 43 years in heterozygous  APOE  ε4 carriers. Homozygous  APOE  ε4 carriers showed a steady decline in CSF Aβ42 concentrations with increasing age throughout the examined age span.    Conclusions  People possessing the  APOE  ε4 allele start to show a decrease in CSF Aβ42 concentration almost a decade before  APOE  ε4 noncarriers already in early middle age. Homozygous  APOE  ε4 carriers might deposit Aβ42 throughout the examined age span. These results suggest that there is an  APOE  ε4-dependent period of early alterations in amyloid homeostasis, when amyloid slowly accumulates, that several years later, together with other downstream pathological events such as tau pathology, translates into cognitive decline.

Preclinical effects of APOE ε4 on cerebrospinal fluid Aβ42 concentrations